alpha-Synuclein (alpha-syn) is a 140-residue
protein of unknown function, involved in several
neurodegenerative disorders, such as
Parkinson's disease. Recently, the possible interaction between alpha-syn and
polyunsaturated fatty acids has attracted a strong interest. Indeed,
lipids are able to trigger the multimerization of the
protein in vitro and in cultured cells.
Docosahexaenoic acid (DHA) is one of the main
fatty acids (FAs) in cerebral gray matter and is dynamically released following
phospholipid hydrolysis. Moreover, it has been found in high levels in brain areas containing alpha-syn inclusions in patients affected by
Parkinson's disease. Debated and unsolved questions regard the nature of the molecular interaction between alpha-syn and DHA and the effect exerted by the
protein on the aggregated state of the FA. Here, we show that alpha-syn is able to strongly interact with DHA and that a mutual effect on the structure of the
protein and on the physical state of the
lipid derives from this interaction. alpha-Syn acquires an alpha-helical conformation in a simple two-state transition. The binding of the
protein to the FA leads to a reduction of the size of the spontaneously formed aggregated species of
DHA as well as of the critical aggregate concentration of the
lipid. Specifically, biophysical methods and electron microscopy observations indicated that the FA forms oil droplets in the presence of alpha-syn. Limited proteolysis experiments showed that, when the
protein is bound to the FA oil droplets, it is initially cleaved in the 89-102 region, suggesting that this chain segment is sufficiently flexible or unfolded to be
protease-sensitive. Subsequent proteolytic events produce fragments corresponding to the first 70-80 residues that remain structured and show high affinity for the
lipid. The fact that a region of the
polypeptide chain remains accessible to
proteases, when interacting with the
lipid, suggests that this region could be involved in other interactions, justifying the ambivalent propensity of alpha-syn towards folding or aggregation in the presence of FAs.